NRITLD Protocol for the Management of Patients with COVID-19 Admitted to Hospitals

This article presents the guideline released by the National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital COVID-19 Expert Group, that aims to help the clinicians caring for patients admitted to hospitals with confirmed or suspected SARS-CoV-2 infection. This guideline includes classification of disease severity, makes use of the indications of a virological assay, of an imaging study, and that of hospital admission. In addition, protocol of treatment is also presented, with chloroquine, lopinavir/ritonavir, remdesivir, favipiravir, umifenovir, oseltamivir, and ribavirin as possible medications, and interferon beta-1a, steroids, intravenous immunoglobulin (IVIG), tocilizumab, and convalescent plasma for severe cases. This guidelines also discusses details on ICU care, hospital discharge planning, and follow up.


Scope of this protocol and ethical issues
The guideline released by the National Research

Classification of severity
The severity of respiratory problems in COVID-19 is defined as follows: Mild: Symptomatic patients without pulmonary infiltration and peripheral capillary oxygen saturation (SpO2) of >93% in ambient air.

Moderate: Patients with pulmonary infiltration and SpO2
of >93% in ambient air.
Severe: Patients with the respiratory rate (RR) of ≥30 breath/minute, SpO2 ≤93% in ambient air, or pulmonary infiltrates in more than 50% of the lung field, not in a critical state.
Critical: Patients admitted to the intensive care unit (ICU); patients who need high flow oxygen with a nasal cannula, noninvasive ventilation, or mechanical ventilation; the ones with acute respiratory distress syndrome (ARDS) or shock (5,6).

Indications of a virologic assay
Virologic assay by reverse transcriptase polymerase chain reaction (RT-PCR) is recommended for any patient with an indication of hospital admission. It is also necessary for symptomatic health care workers taking care of suspected or confirmed cases of COVID-19.
The highest accuracy for the detection of SARS-CoV-2 can be obtained by using the lower respiratory tract specimens. However, the collection of sputum and bronchoalveolar lavage puts the healthcare workers at a higher risk due to aerosols formation. Nasopharyngeal or oropharyngeal swab/wash is the routine method to obtain a specimen for testing. It is reported that the detection of the COVID-19 virus with oropharyngeal swabs was less frequent than nasopharyngeal ones (7).
In Iran, due to restrictions on obtaining nasopharyngeal swabs, the oropharyngeal swabs or washing comprise the majority of respiratory tract specimens.
Clinicians should consider that a single negative RT-PCR is not sufficient to exclude COVID-19, especially if the clinical suspicion is high. Therefore, they should consider test repetition and eventually rely on compatible symptoms, exposure history, and typical CT imaging features for the diagnosis of COVID-19 (8). Although the most sensitive modality is the lung CTscan (10), plain chest x-ray (CXR) may be adequate in normal hosts. For immunocompromised patients, a CTscan of the lung is highly recommended. Routine use of CT-scan, as a screening measure, among asymptomatic cases should highly be deferred (11).

Indications of admission
Indications of in-hospital management are: RR ≥30 breath/minute; SpO2 ≤93% in ambient air, any Mild cases should be managed as an outpatient, but patient education is necessary to come back in the case of deterioration.

-Chloroquine
Chloroquine (in our setting, hydroxychloroquine sulfate), as monotherapy, is recommended for outpatient therapy. It can be prescribed for symptomatic high-risk groups without pneumonia; two tablets b.i.d for the first day and then one tablet b.i.d for 5-10 days (12). In the hospital, when lopinavir/ritonavir is the basic regimen, (13) it is recommended to prescribe hydroxychloroquine just on the first day with a dosage of two tablets b.i.d in order to prevent serious interactions.
In a recent observational study, the administration of hydroxychloroquine was not associated with the decrease of intubation or mortality rates (14). Therefore, recommendations for the prescription of this drug to treat COVID-19 may change in the future.

-Lopinavir/ritonavir
Lopinavir/ritonavir, sold as Kaletra®, is the basic regimen for the cases admitted to hospitals, recommended by the Iranian National COVID-19 Scientific Program. Its efficacy is controversial (4), and in a recent study, no benefit was observed with lopinavir-ritonavir treatment beyond the standard care in hospitalized adult patients with severe COVID-19 (15). It is prescribed as two 200/50 mg tablets b.i.d. Kaletra® causes critical adverse effects and interacts with other drugs. The most serious one is the QT interval prolongation and life-threatening arrhythmia (4). Concomitant administration of drugs with the QT prolongation effects, such as fluoroquinolones, methadon, ondansetron, and metoclopramide, should be avoided in order to prevent arrhythmia. Concomitant administration of Kaletra® with rivaroxaban, lovastatin, simvastatin, colchicine, cisapride, and sildenafil to treat pulmonary artery hypertension is contraindicated (16). It is necessary to get the baseline ECG, and if the corrected QT interval is longer than 500 msec, the drug should be discontinued. For the QT intervals between 450 and 500 msec, the daily repetition of ECG is recommended. Correction of serum electrolytes, such as potassium >4 mEq/L and magnesium >3 mEq/L, is recommended to decrease the chance of arrhythmia (16).
The most frequent problem with Kaletra® is gastrointestinal upset. Taking tablets with food may decrease the chance of this problem (17).
Kaletra® should be prescribed for minimally seven days, but this period can be extended to 14 days (4).

-Remdesivir (as a clinical trial) (IRCT20171122037571N2)
The preliminary findings support the administration of remdesivir to treat hospitalized patients with COVID-19, especially before the disease progression leading patients to require mechanical ventilation (18). Remdesivir is administered intravenously as a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose administered daily for of 5 to 10 days (19,20). there is no specific recommendation in the case of hepatic impairment (4).

-Oseltamivir and Ribavirin
As the recommendation of the National Scientific Committee of COVID-19, and termination of seasonal influenza circulation in the community, oseltamivir is no longer prescribed. Also, ribavirin is withdrawn from the COVID-19 drug regimen in Iran. In the case of the clinician request, one more unit can be transfused after 24 hours for unresponsive cases (34,36,37).

ICU Care
Criteria for the ICU admission of patients with COVID-  There are two types of hypoxic patients with COVID-19   pneumonia  and  different  mechanisms  and pathophysiology, clearly distinguishable by the lung CTscan. In the first group, lung compliance is nearly normal, without ARDS, and in the second, the compliance is low with ARDS. In type 2 patients, in addition to viral pneumonia, they likely have self-induced lung injury due to vigorous inspiratory efforts leading to highly negative intrathoracic pressures and increased edema. Therefore, early intubation and subsequent invasive mechanical ventilation in rapidly progressing respiratory distress can diminish the change from type 1 to type 2 and decrease the risk of self-induced lung injury (39,40).

-Noninvasive ventilation and high flow nasal therapy
We recommend NIV versus early intubation in selected patients with COVID-19 that can tolerate masks, are cooperative, and have no signs of severe respiratory distress. Whenever any intolerance or disadvantages of NIV are suspected, the strategy is changed to the early invasive ventilation protocol.
The main concern about NIV is the aerosol formation and hazard for health care staff (41 Also, ventilation in the prone position is recommended as a rescue maneuver in type 1 and as a long-term treatment in type 2 patients (39). An early tracheostomy with preferred the mini-surgical percutaneous dilatational tracheostomy method is recommended (42).

-Steroid
For the patients admitted to ICU with any stage of ARDS, the prescription of corticosteroids is recommended to decrease the inflammation. The recommended dose is 20 mg dexamethasone daily from day 1 to 5, then 10 mg daily from day 6 to 10. This approach is applied based on the study by Villar et al., (43) in the rapid progression of ARDS in patients with COVID-19 in order not to lose the time.

-Extracorporeal membrane oxygenation
In patients under mechanical ventilation, with Indication of stress ulcer prophylaxis is similar to those of other patients admitted to hospitals.

Hospital discharge planning
The decision to discharge patients is clinical-based.
Overall admission duration of minimally seven days is recommended.
The following criteria are recommended for discharge -Tolerance of oral intake PCR testing before discharge is necessary, but the negative result PCR is not mandatory for patient discharge, although it is preferable.
The patient has to be isolated in his or her house for minimally two weeks. Doctors and nurses should train any patient before discharge from the hospital both verbally and by providing pamphlets, especially in the infection control measures.

Follow-up
If follow-up imaging is necessary, it recommends 6-8 weeks after discharge. The selection of the modality is on the basis of extension of involvement in the previous imaging studies.

Prophylaxis
Currently, there is no evidence of any clinical trial supporting any prophylactic regimen (4). We do not recommend the use of any drug for the prevention of COVID-19 by health care workers or others.